Cardiovascular disease affects millions of people per year. One aspect of cardiovascular disease is hyperlipidemia, a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL cholesterol levels. Although it is desirable to lower elevated levels of LDL cholesterol, it is also desirable to increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See, for example, Gordon, et al., Am. I. Med., 62:707-714 (1977); Stampfer, et al., N. England J. Med., 325:373-381 (1991); and Kannel, et al., Ann. Internal Med., 90:85-91 (1979).
Plasma HDL-cholesterol concentrations are inversely related to atherosclerosis (see, e.g., Gordon et al., Am. J. Med. 62:707-714 (1977) and Rifkind, Am. J. Cardiol. 66:3A-6A (1990)). The beneficial effects of HDL are attributed, in part, to its role in reverse cholesterol transport (RCT), an important anti-atherogenic pathway. The rate-limiting, first-step of RCT involves the efflux of cholesterol from macrophage foam-cells in the artery wall mediated by apoA-I, the major HDL apolipoprotein (see, e.g., Rothblat and Phillips, Curr. Opin. Lipidol. 2:288-294 (1991) and Fielding and Fielding, J. Lipid Res. 36:211-228 (1995)). Cholesterol efflux mediated by apoA-I generates nascent HDL and reverses the macrophage foam-cell phenotype. For these reasons, cellular cholesterol efflux is clinically relevant representing an attractive target of therapeutic interventions for combating atherosclerosis. Recently a synthetic form of HDL was found to rapidly regress atherosclerotic lesions in humans suffering from acute coronary syndrome, providing evidence that therapeutics based on HDL may be efficacious in the treatment of heart disease (Nissen et al., JAMA 290:2292-2300 (2003)). Developing the next generation of advanced therapeutics based on HDL requires detailed knowledge of the underlying molecular mechanisms by which apoA-I stimulates cellular cholesterol efflux and initiates RCT.
Mutations in the ATP-binding cassette transporter A1 (ABCA1) as found in Tangier Disease abolish the ability of apoA-I to promote cellular cholesterol efflux (see, e.g., Francis et al., J. Clin. Invest. 96: 78-87 (1995); Remaley et al., Arterioscler. Thromb. Vasc. Biol. 17:1813-1821 (1997); Brooks-Wilson et al., Nature Genetics, 22:336-344 (1999); and Bodzioch et al., Nature Genetics, 22:347-351 (1999)). Human subjects with Tangier Disease have increased risk for developing premature atherosclerosis resulting from a deficiency in HDL (see, e.g., Brooks-Wilson et al., Nature Genetics, 22:336-344 (1999); Bodzioch et al., Nature Genetics, 22:347-351 (1999); Schaefer et al., Ann. Intern. Med. 93:261-266 (1983); Serfaty-Lacrosniere et al., Atherosclerosis 107:85-98 (1994); and Hobbs and Rader, J. Clin. Invest. 104:1015-1017 (1999)). Studies of Tangier Disease provide compelling evidence that ABCA1-dependent cholesterol efflux is required for HDL biogenesis in humans. Targeted disruption of the ABCA1 gene in mice produces a phenotype similar to human Tangier Disease while over-expression of ABCA1 protects against atherosclerosis, underscoring the importance of apoA-I/ABCA1 interactions in heart disease protection (see, e.g., McNeish et al., Proc. Natl. Acad. Sci. 97:4245-4250 (2000) and Singaraja et al., J. Biol. Chem. 277:22426-22429 (2002)). Apo A-I also stabilizes cellular ABCA1 protein preventing its degradation (Wang et al., J. Clin. Invest. 111:99-107 (2003); Martinez et al., J. Biol. Chem. 278:37368-37374 (2003); and Wang et al., J. Biol. Chem. 275: 33053-33058 (2000)). This represents a mechanism for up-regulating ABCA1 protein, one potential target of therapeutic intervention to optimizing cholesterol efflux and HDL assembly.
Identifying key amino acids and unique aspects of amphipathic α-helices of Apo A-I and other apolipoproteins that are required to stimulate ABCA-dependent cholesterol efflux may provide for the design of therapeutics to combat atherosclerosis and other disorders of where mediation of cholesterol efflux is desirable, i.e., diseases and disorders associated with dyslipidemia such as, e.g., heart disease, atherosclerotic lesions, stroke, Alzheimer's, and storage disorders.
Thus, there is a need in the art for additional compositions and methods for treating cardiovascular disease, i.e., by mediating cholesterol efflux, stabilizing ABCA. The present invention meets these and other needs.